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Open Access Research article

The statistical analysis of a clinical trial when a protocol amendment changed the inclusion criteria

Christian Lösch1* and Markus Neuhäuser12

Author Affiliations

1 Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany

2 Department of Mathematics and Technique, RheinAhrCampus, Koblenz University of Applied Sciences, Südallee 2, 53424 Remagen, Germany

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BMC Medical Research Methodology 2008, 8:16  doi:10.1186/1471-2288-8-16

Published: 8 April 2008

Abstract

Background

Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Then, the patient populations before and after the amendment may differ.

Methods

We propose to perform separate statistical tests for the different phases, i.e. for the patients recruited before and after the amendment, and to combine the tests using Fisher's combination test. After a significant combination test a multiple testing procedure can be applied to identify the phase(s) to which a proof of efficacy refers. We assume that the amendment(s) are not based on any type of unblinded data. The proposed method is investigated within a simulation study.

Results

The proposed combination approach is superior to the 'naïve' strategy to ignore the differences between the phases and pooling the data to perform just one statistical test. This superiority disappears when there are hardly any differences between the two phases.

Conclusion

When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ. In this case, separate tests for the different phases together with a combination test are a powerful method that can be applied in a variety of settings. The (first) amendment should specify the combination test to be applied in order to combine the different phases.